Andrew Clark

Spray Dried Powders and Powder Blends of Recombinant Human Deoxyribonuclease (rhDNase) for Aerosol Delivery

AbstractPurpose. We have used rhDNase to investigate the feasibility of developing a dry protein powder aerosol for inhalation delivery.nMethods. Powders of rhDNase alone and with sodium chloride were prepared by spray drying. Powder blends were obtained by mixing (tumbling and sieving) pure rhDNase powder with carrier materials (lactose, mannitol or sodium chloride). The weight percent of drug in the blends was between 5 and 70%. The particle size distributions and crystallinity of the spray dried powders were obtained by laser diffraction and X-ray powder diffraction, respectively. Particle morphology was examined by scanning electron microscopy. The ability of the powders and powder blends to be dispersed into respirable aerosols was measured using a Rotahaler™ connected to a multistage liquid impinger operating at 60 L/min.nResults. Pure rhDNase powder was quite cohesive with a fine particle fraction (FPF or respirable fraction: % wt. of particles < 7 μm in the aerosol cloud) of about 20%. When particles also contained NaCl, the powders were dispersed better to form aerosols. A linear relationship was observed between the NaCl content and FPF for a similar primary size (~3 μm volume median diameter) of particles. The particle morphology of these powders varied systematically with the salt content. For the blends, SEM revealed a monolayer-like adhesion of the fine drug particles to the carriers at drug contents ≥50 % wt. An overall 2-fold increase in FPF of rhDNase in the aerosol cloud was obtained for all the blends compared to the pure drug aerosols.nConclusions. The aerosol properties of spray dried rhDNase powders can be controlled by incorporation of a suitable excipient, such as NaCl, and its relative proportion. Coarse carriers can also enhance the performance of rhDNase dry powder aerosols.

The effect of inhaling a dry powder of sodium chloride on the airways of asthmatic subjects

Wet aerosols of 4.5% sodium chloride (NaCl) are often used to assess the bronchial responsiveness associated with asthma. We questioned whether dry NaCl could be used as an alternative. Dry powder NaCl was inhaled from capsules containing either 5, 10, 20 or 40 mg to a cumulative dose of 635 mg. The powder was delivered via an Inhalator or Halermatic. The airway sensitivity to the dry and wet NaCl was compared in 24 patients with asthma aged 19-39 yrs. All subjects responded to both preparations and the geometric mean (95% confidence intervals) for the provocative dose of NaCl causing forced expiratory volume in one second (FEV1) to fall 20% from baseline (PD[20,NaCl]) for dry NaCl was 103 mg (68-157) versus 172 mg (102-292), p<0.03 for the wet NaCl. The response to dry NaCl was reproducible and on repeat challenge the PD20 was 108 mg (75-153). The mean maximum fall in FEV1 was approximately 25% on each of the two test days. Spontaneous recovery occurred within 60 min after challenge with dry NaCl and within 5 min after bronchodilator. There were no serious side-effects requiring medical attention, however some patients coughed on inhalation of the 40 mg dose and three gagged. Arterial oxygen saturation remained within normal limits. We conclude that a suitably prepared dry powder of sodium chloride could potentially replace wet sodium chloride to assess bronchial responsiveness in patients with asthma, but further studies are required to establish the long-term stability of the dry powder preparation.

Deposition, Imaging, and Clearance: What Remains to be Done?

Deposition and clearance studies are used during product development and in fundamental research. These studies mostly involve radionuclide imaging, but pharmacokinetic methods are also used to assess the amount of drug absorbed through the lungs, which is closely related to lung deposition. Radionuclide imaging may be two-dimensional (gamma scintigraphy or planar imaging), or three-dimensional (single photon emission computed tomography and positron emission tomography). In October 2009, a group of scientists met at the Thousand Years of Pharmaceutical Aerosols conference in Reykjavik, Iceland, to discuss future research in key areas of pulmonary drug delivery. This article reports the session on Deposition, imaging and clearance. The objective was partly to review our current understanding, but more importantly to assess what remains to be done? A need to standardize methodology and provide a regulatory framework by which data from radionuclide imaging methods could be compared between centers and used in the drug approval process was recognized. There is also a requirement for novel radiolabeling methods that are more representative of production processes for dry powder inhalers and pressurized metered dose inhalers. A need was identified for studies to aid our understanding of the relationship between clinical effects and regional deposition patterns of inhaled drugs. A robust methodology to assess clearance from small conducting airways should be developed, as a potential biomarker for therapies in cystic fibrosis and other diseases. The mechanisms by which inhaled nanoparticles are removed from the lungs, and the factors on which their removal depends, require further investigation. Last, and by no means least, we need a better understanding of patient-related factors, including how to reduce the variability in pulmonary drug delivery, in order to improve the precision of deposition and clearance measurements.

Understanding penetration index measurements and regional lung targeting.

Radiolabeling of pharmaceutical inhalation aerosols began in the late 1970s. Since then, well over 100 studies have been published. These studies have documented lung deposition for all inhalation dosage forms; pressurized metered dose inhalers (pMDIs), dry powder inhalers (DPIs), soft mist inhalers (SMIs), and nebulizers. They have provided valuable insight into the factors that influence total and regional lung deposition. Taken globally, this collection of data has recently been used to elucidate the influence of intersubject variability in head geometry on total lung deposition, showing good correspondence between theory and experiment. The analysis reported here is an attempt to take this data set one step deeper into the airways and understand the relationship between P/C ratio, derived from 2D imaging, and a more anatomically relevant biological distribution within the lung, 24-h clearance. Intersubject variability in regional deposition is also analyzed, although due to the sparse nature of the reported individual data only tentative conclusions can be drawn. Many different techniques for derivation and analysis of scintigraphic data have been reported in the literature, and this leads to some difficulties when performing the meta-analyses reported below. In this regard it is recommended that standardization of scintigraphy techniques should be a future goal.

In Vitro Assessment of Dose Delivery Performance of Dry Powders for Inhalation

The aerosol performance of engineered porous particles (PulmoSphere™) for inhalation as a function of powder properties (particle size and density) was assessed using an idealized replica of the adult human upper respiratory tract (URT) known as the Alberta mouth-throat model. Engineered placebo powders were prepared using the PulmoSphere™ technology, which is based on spray-drying an emulsion feedstock and produces porous particles with well-controlled size and density. These placebo powders are useful surrogates for a class of potent active formulations, and covered a range of particle sizes and densities, representing a particle design space relevant to dry powder inhalers. The Alberta idealized mouth-throat model was used for in vitro measurement of oropharyngeal (mouth and throat) losses and to estimate the total lung dose for different inhalation drug products. The in vitro lung doses measured with the mouth-throat model were compared to predictions of lung dose from semi-empirical numerical models of oropharyngeal deposition. Data from the mouth-throat model and numerical models were used to rank order oropharyngeal losses and flow-rate dependence in the 1–6 kPa pressure drop range. Aerosol performance of the PulmoSphere™ powders was favored by low-particle density and large geometric size, with the oropharyngeal deposition and flow rate dependence being lower for powders with median particle diameter ≥2.5 microns. In comparison, data from lactose-blend formulations showed significantly higher oropharyngeal deposition and flow rate dependence. The idealized mouth-throat model provides a reasonable in vitro estimate of dose delivered to the lungs, and is a useful tool for studying the effect of factors such as drug/device and inhalation airflow. Copyright 2014 American Association for Aerosol Research